WVE-004 / Wave Life Sciences, Takeda - LARVOL DELTA

Compassionate use of C9ORF72 targeted ASOs in ALS – experience from eight patients at three German centers (ALS-MND 2025) - P1, P1b/2a | "Disease modifying therapies are limited, but recently an ASO against another form of autosomal dominantly inherited ALS, tofersen (Qalsody) against SOD1, has demonstrated clinical and biomarker (neurofilament, NfL) efficacy...In contrast, two industry programs testing ASOs targeting C9ORF72, (BIIB078, Biogen/Ionis) and (WVE004, Wave), were discontinued after disappointing results of the corresponding phase 1/2 trials (NCT03626012 and NCT04931862)... Our C9ORF72 ASO (Afinersen), which targets both the sense and anti-sense strands of C9ORF72, is well tolerated and produces robust target engagement at (>70% polyGP lowering after six months of treatment) and has a favorable risk profile and long-term tolerability in patients with C9ORF72 familial ALS. Treatment associated clinical and biomarker effects were monitored and the primary results of these analyses and interpretation of our experience will be presented at the conference. In our view, these data..."

Clinical • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia

Drug discovery research with the iPSC models of neurodegenerative diseases. (PubMed, Neurosci Res) - "In addition, clinical trials based on research with iPSCs have been conducted: bosutinib, ropinirole and ezogabine for ALS, WVE-004 and BIIB078 for ALS with frontotemporal dementia (ALS/FTD), and bromocriptine for familial AD. Finally, we also wish to mention screening studies utilizing artificial intelligence (AI)."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration

FOCUS-C9: Study of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD) (clinicaltrials.gov) - P1b/2a | N=35 | Terminated | Sponsor: Wave Life Sciences Ltd. | Trial completion date: Dec 2023 ➔ Jun 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2023 ➔ Jun 2023; Despite robust, sustained reductions in poly(GP), no clinical benefit was seen at 24 weeks, and reductions in poly(GP) were not associated with stabilization in functional outcomes. Based on these data, Wave decided to stop development of WVE-004.

Trial completion date • Trial primary completion date • Trial termination • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration

Open-label Extension (OLE) Study of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD) (clinicaltrials.gov) - P1/2 | N=8 | Terminated | Sponsor: Wave Life Sciences Ltd. | N=42 ➔ 8 | Trial completion date: Feb 2026 ➔ Jun 2023 | Enrolling by invitation ➔ Terminated | Trial primary completion date: Feb 2026 ➔ Jun 2023; Despite robust, sustained reductions in poly(GP), no clinical benefit was seen at 24 weeks, and reductions in poly(GP) were not associated with stabilization in functional outcomes. Based on these data, Wave decided to stop development of WVE-004.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration

Wave Life Sciences Announces Topline Results from Phase 1b/2a FOCUS-C9 Study of WVE-004 for C9orf72-associated Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (GlobeNewswire) - P1b/2a | N=35 | FOCUS-C9 (NCT04931862) | Sponsor: Wave Life Sciences Ltd. | "Wave Life Sciences...today announced topline results from the Phase 1b/2a FOCUS-C9 study evaluating WVE-004 as an investigational treatment for C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). The results include data from a planned analysis of the study, where participants received multiple 10 mg doses of WVE-004 or placebo every 12 weeks (Q12W) or every 4 weeks (Q4W), as well as an additional 20 mg single dose cohort....Wave remains on track to share data from its Phase 1b/2a SELECT-HD study in Huntington’s disease investigating WVE-003 in the second half of 2023....WVE-006, into a clinical trial in Alpha-1 antitrypsin deficiency in the second half of 2023. In addition, the company continues to advance preclinical research with its modalities that restore or repair endogenous proteins, including additional RNA editing programs."

New trial • P1/2 data • Preclinical • Alpha-1 Antitrypsin Deficiency • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Genetic Disorders • Huntington's Disease

FOCUS-C9: Study of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD) (clinicaltrials.gov) - P1b/2a | N=35 | Active, not recruiting | Sponsor: Wave Life Sciences Ltd. | Recruiting ➔ Active, not recruiting | Trial completion date: Feb 2023 ➔ Dec 2023 | Trial primary completion date: Feb 2023 ➔ Dec 2023

Enrollment closed • Trial completion date • Trial primary completion date • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology

Open-label Extension (OLE) Study of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD) (clinicaltrials.gov) - P1/2 | N=42 | Enrolling by invitation | Sponsor: Wave Life Sciences Ltd.

New P1/2 trial • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology

Wave Life Sciences Reports Third Quarter 2022 Financial Results and Provides Business Update (GlobeNewswire) - “Key Anticipated Upcoming Milestones: WVE-003 for HD: Additional single-dose biomarker and safety clinical data expected in 1H 2023; WVE-004 for C9-ALS and C9-FTD: Clinical data from all cohorts in the FOCUS-C9 trial expected in 1H 2023….Research and development expenses were $27.6 million in the third quarter of 2022 as compared to $31.1 million in the same period in 2021. The decrease in research and development expenses in the third quarter was primarily due to decreased external expenses related to our HD programs...”

Biomarker • Commercial • P1/2 data • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration • Huntington's Disease

Wave Life Sciences Reports Second Quarter 2022 Financial Results and Provides Business Update (GlobeNewswire) - “Key Anticipated Upcoming Milestones: WVE-004 for C9-ALS and C9-FTD: Additional single and multidose clinical data for WVE-004 expected in 2H 2022. Planning underway to initiate an open-label extension (OLE) clinical trial in 2H 2022. WVE-003 for HD: Clinical data expected in 2H 2022 for WVE-003 to provide further insight into the clinical effects of PN chemistry and enable decision-making for this program….Research and development expenses were $29.7 million in the second quarter of 2022 as compared to $31.6 million in the same period in 2021. The decrease in research and development expenses in the second quarter was primarily due to decreased external expenses related to our previously disclosed discontinued PRECISION-HD programs…”

Commercial • New trial • P1/2 data • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration • Huntington's Disease

Preclinical evaluation of WVE-004, aninvestigational stereopure oligonucleotide forthe treatment of C9orf72-associated ALS or FTD. (PubMed, Mol Ther Nucleic Acids) - "These in vivo effects were durable, persisting for at least 6 months. These data support the advancement of WVE-004 as an investigational stereopure antisense oligonucleotide targeting C9orf72 for the treatment of C9orf72-associated ALS or FTD."

Journal • Preclinical • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology

Wave Life Sciences Reports First Quarter 2022 Financial Results and Provides Business Update (GlobeNewswire) - “Wave plans to share…clinical data in an oral presentation at the upcoming European Network to Cure ALS (ENCALS) Meeting in Edinburgh, Scotland, which is taking place June 1 – 3, 2022….Key Anticipated 2022 Milestones: WVE-004 for C9-ALS and C9-FTD: Additional single and multidose clinical data for WVE-004 expected throughout 2022. Wave expects to use these data to optimize WVE-004 dose level and frequency, as well as to enable discussions with regulatory authorities regarding the next phase of development later in 2022. Planning underway to initiate an open-label extension (OLE) clinical trial in mid-2022….Research and development expenses were $27.5 million in the first quarter of 2022…The decrease in research and development expenses in the first quarter was primarily due to decreased external expenses related to our previously disclosed discontinued PRECISION-HD programs…”

Commercial • New trial • P1/2 data • Regulatory • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration • Huntington's Disease

Wave Life Sciences Announces Publication of Foundational Preclinical Data Supporting Development of WVE-004 for C9orf72-associated ALS and FTD (GlobeNewswire) - “Wave Life Sciences Ltd…announced the publication of preclinical data for WVE-004, the company’s clinical candidate for C9orf72-associated amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD), in Molecular Therapy Nucleic Acids (MTNA). The paper includes in vivo data demonstrating that WVE-004 led to potent, sustained reductions in pathogenic C9orf72 RNA transcripts and poly(GP) dipeptide repeat proteins (DPRs) for six months in C9 BAC transgenic mice after only two doses, without altering C9orf72 protein levels.”

Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration

Wave ALS Update Delights Industry Observers, Investors (BioSpace) - “Researchers in WAVE Life Sciences' Phase Ib/IIa study on a potential treatment for amyotrophic lateral sclerosis (ALS) shared a positive update on the drug's disease-targeting abilities. The ongoing FOCUS-C9 trial showed that WVE-004, the clinical candidate for C9-ALS and frontotemporal dementia (C9-FTD), remained effective across the various dose levels tested….The company's shares rose by 29.6% on NASDAQ shortly after the announcement.”

P1/2 data • Stock price • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration

Wave Life Sciences Announces Positive Update to Ongoing Phase 1b/2a FOCUS-C9 Study Driven by Potent, Durable Reductions of Poly(GP) with Low, Single Doses of WVE-004 (GlobeNewswire) - P1/2 | N=42 | FOCUS-C9 (NCT04931862) | Sponsor: Wave Life Sciences Ltd. | “Wave Life Sciences Ltd…announced a positive update to the ongoing Phase 1b/2a FOCUS-C9 trial of WVE-004, the company’s clinical candidate for C9orf72-associated amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD)….The trial update announced today is being driven by the observation of potent, durable reductions of poly(GP) dipeptide repeat proteins in cerebrospinal fluid (CSF) with low, single doses of WVE-004….Reductions in poly(GP) were observed across all active treatment groups (10 mg, n=2 patients; 30 mg, n=4 patients; 60 mg, n=3 patients), reaching statistical significance versus placebo (n=3 patients) after single 30 mg doses, with a 34% reduction in poly(GP) at day 85 (p=0.011)…and additional single and multidose data are expected throughout 2022.”

P1/2 data • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration

Wave Life Sciences Reports Fourth Quarter and Full Year 2021 Financial Results and Provides Business Update (GlobeNewswire) - “WVE-004 for C9orf72-associated amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD): FOCUS-C9 is an ongoing, double-blind, adaptive, Phase 1b/2a clinical trial of WVE-004. WVE-003 targeting SNP3 for Huntington’s disease (HD): SELECT-HD is an ongoing, double-blind, adaptive, Phase 1b/2a clinical trial of WVE-003. Upcoming clinical milestones: Wave expects to share clinical data in 2022 for WVE-004, WVE-003…to provide insight into the clinical effects of PN chemistry and enable decision-making for each program.”

P1/2 data • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration • Huntington's Disease

Wave Life Sciences Announces Initiation of Dosing in Phase 1b/2a FOCUS-C9 Clinical Trial of WVE-004 in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (GlobeNewswire) - “Wave Life Sciences…announced that multiple participants have initiated dosing in the Phase 1b/2a FOCUS-C9 clinical trial evaluating WVE-004 as an investigational treatment for C9orf72-associated amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD).’…We anticipate generating clinical data in 2022…’”

P1/2 data • Trial status • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration

Phase 1b/2a Study of WVE-004 in Patients with C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD) (clinicaltrialsregister.eu) - P1/2; N=42; Ongoing; Sponsor: Wave Life Sciences UK Limited

Clinical • New P1/2 trial • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Cognitive Disorders • Complement-mediated Rare Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology

Wave Life Sciences Reports First Quarter 2021 Financial Results and Provides Business Update (GlobeNewswire) - "This week, at the European Network to Cure ALS (ENCALS) meeting being held May 12 – May 14, Wave is presenting a poster introducing its FOCUS-C9 Phase 1b/2a trial design for WVE-004...clinical trial to assess the safety and tolerability of intrathecal doses of WVE-004 for patients with C9-ALS and/or C9-FTD....Research and development expenses were $33.4 million in the first quarter of 2021...the increases in external expenses related to Wave’s clinical and preclinical activities related to its HD programs and its C9orf72 program for ALS and FTD."

Commercial • P1/2 data • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration

"WVE004 looks a really promising therapy for c9orf72 patients. When are you expecting to receive the FDA approval?" (@ilariaghiro)

Clinical • FDA event

[VIRTUAL] WVE-004, an investigational stereopure antisense oligonucleotide for the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (AAN 2021) - "In transgenic mice, WVE-004 produces substantial reductions in repeat-containing C9orf72 transcripts and DPR proteins without disrupting total protein expression, sustained for at least 6 months. These results support further development of WVE-004 in patients with C9orf72-associated ALS and FTD."

Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration

Wave Life Sciences Reports Fourth Quarter and Full Year 2020 Financial Results and Provides Business Update (GlobeNewswire) - "Wave expects to initiate dosing in a Phase 1b/2a clinical trial of WVE-004 for both patients with C9-ALS and patients with C9-FTD in 2021....Research and development expenses were $30.0 million in the fourth quarter of 2020...Research and development expenses were $130.9 million in 2020...decreases in compensation-related expenses and other external expenses driven by Wave's February 2020 cost reduction plan, partially offset by the increases in external expenses related to Wave’s clinical and preclinical activities related to its HD programs and its C9orf72 program for ALS and FTD."

Commercial • New P1/2 trial • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration

[VIRTUAL] WVE-004, an Investigational Stereopure Antisense Oligonucleotide for the Treatment of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (MDA 2021) - No abstract available

Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology

[VIRTUAL] WVE-004, an investigational stereopure antisense oligonucleotide for the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (MDA 2021) - "In transgenic mice, WVE-004 produces substantial reductions in repeat-containing C9orf72 transcripts and DPR proteins without disrupting total protein expression, sustained for at least 6 months. These results support further development of WVE-004 in patients with C9orf72-associated ALS and FTD."

Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology

Wave Life Sciences Highlights Pipeline Progress and Expansion Leveraging New PN Backbone Chemistry Modifications (GlobeNewswire) - “‘We also plan to deliver comprehensive data results from the ongoing PRECISION-HD trials late in the first quarter to enable a decision regarding potential Phase 3 development for WVE-120101 and WVE-120102...' Wave expects to initiate dosing in three proof-of-concept studies in 2021, which will assess target engagement, impact on key disease biomarkers, and initial safety for WVE-003 in Huntington’s disease (HD), WVE-004 in amyotrophic lateral sclerosis (ALS)…In December 2020, Wave submitted a CTA for WVE-004. Wave expects to initiate dosing in ALS and FTD patients with G4C2 expansions in 2021.”

New trial • P3 data • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration • Huntington's Disease

Wave Life Sciences Reports Third Quarter 2020 Financial Results and Provides Business Update (GlobeNewswire) - “‘…on track to file clinical trial applications for WVE-003 for Huntington’s disease and WVE-004 for amyotrophic lateral sclerosis and frontotemporal dementia this quarter.’…Wave is developing a third allele-selective HD candidate, WVE-003, which is designed to selectively target an undisclosed SNP on the mHTT mRNA transcript (SNP3), while leaving wtHTT protein relatively intact….Wave expects to initiate clinical development of WVE-004 with the submission of a CTA in the fourth quarter of 2020….Wave expects to initiate clinical development of WVE-003 with the submission of a clinical trial application (CTA) in the fourth quarter of 2020.”

New trial • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease